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Mol Genet Metab. 2012 Nov;107(3):438-47. doi: 10.1016/j.ymgme.2012.07.025. Epub 2012 Aug 6.

Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations.

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1
Biochimie - Hôpital de Bicêtre, Hôpitaux Universitaires Paris-Sud, APHP-Paris, France. audrey.boutron@bct.aphp.fr

Abstract

BACKGROUND:

Classic galactosemia refers to galactose-1-phosphate uridyltransferase (GALT) deficiency and is characterized by long-term complications of unknown mechanism and high allelic heterogeneity of GALT gene.

AIM:

To report molecular characterization of GALT variations in 210 French families, to analyze the structural effects of novel missense variations and to assess informativity of structural data in predicting outcome.

METHODS:

Sequencing of exons and intron-exon junctions of GALT gene was completed in unsolved cases by analysis of a long range PCR product. Structural consequences of novel missense variations were predicted using a homology model of GALT protein and a semi-automated analysis which integrates simulation of variations, structural analyses and two web servers dedicated to identify mutation-induced change of protein stability.

RESULTS:

Forty four novel variations were identified, among them 27 nucleotide substitutions. In silico modeling of these missense variations showed that 12 variations are predicted to impair subunit interactions and/or active site conformation and that 23 variations modify H-bond or salt-bridge networks. Twenty variations decrease the global stability of the protein. Five variations had apparently no structural effect.

CONCLUSION:

Our results expand the mutation spectrum in GALT gene and the list of GALT variations analyzed at the structural level, providing new data to assess the pathophysiology of galactosemia.

PMID:
22944367
DOI:
10.1016/j.ymgme.2012.07.025
[Indexed for MEDLINE]
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